Disease relevance of Prkcm

• Mutations of either PKD1 or PKD2 are associated with autosomal dominant polycystic kidney disease (ADPKD) [1].
• Polycystin 1, the product of the PKD1 gene, is mutated in autosomal dominant polycystic kidney disease, a disease characterized by renal cyst formation and progressive renal failure [2].
• Polycystic kidney disease (PKD) is associated with mutations in PKD1 and PKD2 and vascular abnormalities [3].
• Homozygote embryos (Pkd1(-/-)) developed hydrops, cardiac conotruncal defects and renal cystogenesis [1].
• In order to generate Swiss 3T3 cells stably overexpressing PKD, cultures of these cells were infected with retrovirus encoding murine PKD and green fluorescent protein (GFP) expressed as two separate proteins translated from the same mRNA [4].

High impact information on Prkcm

• Mouse embryos lacking Pkd1 have defective STAT1 phosphorylation and p21(waf1) induction [5].
• Mice heterozygous and homozygous for this mutation, as well as Pkd+/- mice, develop polycystic kidney and liver lesions that are indistinguishable from the human phenotype [6].
• The vasopressin V2 receptor (VPV2R) antagonist OPC31260 has been effective in two animal models of PKD with pathologies that are probably related [7].
• Protein kinase D (PKD) is an antigen receptor-activated serine kinase localized at either the plasma membrane or the cytosol of lymphocytes [8].
• Membrane but not cytosolic PKD could induce expression of CD8 and CD4 in recombinase null mice; cytosolic but not membrane PKD suppressed Vbeta to DJbeta rearrangements of the TCRbeta chain locus in wild-type T cells [8].

Chemical compound and disease context of Prkcm

• Both of these channels belong to the larger polycystic kidney disease (PKD or TRPP) subfamily of TRP channels, members of which have been demonstrated to be non-selective cation channels and permeable to both Na(+) and Ca(2+) [9].
• Lysophosphatidic acid rapidly induces protein kinase D activation through a pertussis toxin-sensitive pathway [10].

Biological context of Prkcm

• Associated with this inhibitory effect of Go6976, BMP-2 induced a selective and a dose-dependent Ser916 phosphorylation/activation of PKD, which was also blocked by Go6976 [11].
• Expression of the protein kinase D (PKD) family during mouse embryogenesis [12].
• These data indicate that PKD1 influences cell migration by directing vesicular transport of the alphavbeta3 integrin heterodimer [13].
• The catalytic domain of PKD contains all characteristic sequence motifs of serine protein kinases but shows only a low degree of sequence similarity to PKCs [14].
• PKD contains membrane localization signals and a cysteine-rich repeat sequence homologous to that seen in the regulatory domain of protein kinase C (PKC) [14].

Anatomical context of Prkcm

• Upon heterologous expression PKDREJ was retained in intracellular membrane compartments and unlike PKD1 did not undergo cleavage in the G-protein-coupled receptor proteolytic site domain (GPS) [15].
• The cystogenesis of ADPKD is believed to be a monoclonal proliferation of PKD-deficient (PKD(-/-)) renal tubular epithelial cells [16].
• PKD1/PKCmu promotes alphavbeta3 integrin recycling and delivery to nascent focal adhesions [13].
• We had found that the activation loop of a PKD mutant, with reduced affinity for diacylglycerol and phorbol esters, was only phosphorylated upon its plasma membrane association [17].
• COS-7 cells transfected with a PKD cDNA construct (pcDNA3-PKD) exhibit a marked (4.8-fold) increase in [3H]phorbol 12,13-dibutyrate binding [18].

Associations of Prkcm with chemical compounds

• The bacterially expressed catalytic domain of PKD efficiently phosphorylated the exogenous peptide substrate syntide 2 in serine but did not catalyze significant phosphorylation of a variety of other substrates used by PKCs and other major second messenger regulated kinases [14].
• A novel protein kinase (named PKD) with an NH2-terminal region containing two cysteine-rich motifs has been expressed in COS-7 cells and identified as a receptor for phorbol esters [18].
• The substrate specificity of PKD is different from that of previously identified members of the protein kinase C family since it does not efficiently phosphorylate histone III-S, protamine sulfate, or a synthetic peptide based upon the conserved pseudosubstrate region of the protein kinase C family [18].
• Co-expression studies revealed a pro-proliferative, anti-differentiative effect of PKD on keratinocyte maturation as monitored by increased and decreased promoter activities of keratin 5, a proliferative marker, and involucrin, a differentiative marker, respectively [19].
• Treatment with pioglitazone improved survival of Pkd1(-/-) embryos and ameliorated the cardiac defects and the degree of renal cystogenesis [1].

Other interactions of Prkcm

• It is caused by mutations in PKD1 or PKD2, encoding polycystin-1 and -2, which together form a cell surface nonselective cation ion channel [20].
• The present study focuses on a PKD1 homologue, mouse polycystic kidney disease and receptor for egg jelly (PKDREJ) and its putative role in mammalian fertilization [15].
• Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD [21].
• PKD has been the focus of most studies up to date, but little is known about the mechanisms that mediate PKD3 activation [22].
• We also found that the activation loop phosphorylation and rapid plasma membrane dissociation of PKD were inhibited either by preventing the plasma membrane translocation of PKCepsilon, through abolition of its interaction with receptor for activated C kinase, or by suppressing the expression of PKCepsilon via specific small interfering RNAs [17].

Analytical, diagnostic and therapeutic context of Prkcm

• Using specific probe sets for RT-PCR and in situ hybridization, we demonstrate shared and differential expression domains for the three PKD family members in both neuronal and non-neuronal tissues [12].
• Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain [14].
• Antigen receptor ligation of T and B lymphocytes also induced phosphorylation of the serine 916 residue of PKD/PKCmu [23].
• To probe PKD function at these different locations, transgenesis was used to target active PKD either to the membrane or cytosol of pre-T cells [8].
• By studying the putative involvement of lipid rafts in PKD activation and signaling we have found that active PKD partitions in lipid raft fractions after sucrose gradient centrifugation and that green fluorescent protein-PKD translocates to lipid raft microdomains at the plasma membrane after phorbol ester treatment [24].

References